Derivatives of 2-hydroxymethyl-1,3,4-oxadiazole

ABSTRACT

Compounds of the formula   WHEREIN R1 is hydrogen, aminocarbonyl or aminocarbonyl Nsubstituted by alkyl having up to 4 carbon atoms, R2 is halogen, alkoxy having up to 4 carbon atoms, alkyl having up to 4 carbon atoms, or trifluoromethyl N IS 0, 1, 2 OR 3 ARE PREPARED BY REACTING ETHYL HYDROXYACETIMIDATE HYDROCHLORIDE WITH PHENYLHYDRAZIDE OR (R2)n-substituted phenylhydrazide. When R1 is other than hydrogen, that reaction product is reacting with an alkyl isocyanate, or reacted with phenylchloroformate followed by reaction with ammonia. The compounds possess analgesic, antiinflammatory, anticonvulsivant, tranquilizing, myorelaxant, antidepressive, vasodilatatory, diuretic, anti-ulcerous, antiarythmic, antiserotoninic, spasmolytic, hypotensive, antibronchocontrictive, anticholinergic and antiemetic properties.

United States Patent [191 Huguet et al.

[54] DERIVATIVES OF I ZHYDROXYNIETHYL-LSA-OXADIAZOLE [73] Assignee:Delalande S.A., Courbevoie, France [22] Filed: Jan. 25, 1974 [21] Appl.No.: 436,694

[30] Foreign Application Priority Data OTHER PUBLICATIONS Wagner et al.,Synthetic Organic Chemistry, Wiley & Sons, lnc., New York, (I953), p.645.

Morrison et 211., Organic Chemistry, Allyn & Bacon, Inc., Boston,(1959), pp. 482-484.

Primary Examiner-Raymond V. Rush Attorney, Agent, or FirmWoodhams,Blanchard and Flynn [57] ABSTRACT Compounds of the formula wherein R ishydrogen, aminocarbonyl or aminocarbony] N-substituted by alkyl havingup to 4 carbon atoms,

R is halogen, alkoxy having up to 4 carbon atoms, alkyl having up to 4carbon atoms, or trifluoromethyl n is O, l, 2 or 3 are prepared byreacting ethyl hydroxyacetimidate hydrochloride with phenylhydrazide or(R ),,substituted phenylhydrazide. When R is other than hydrogen, thatreaction product is reacting with an alkyl isocyanate, or reacted withphenylchloroformate followed by reaction with ammonia. The compoundspossess analgesic, antiinflammatory, anticonvulsivant, tranquilizing,myorelaxant, antidepressive, vasodilatatory, diuretic, anti-ulcerous,antiarythmic, antiserotoninic, spasmolytic, hypotensive,antibronchocontrictive, anticholinergic and antiemetic properties.

19 Claims, No Drawings DERIVATIVES OF I 2-HYDROXYMETHYL- l,3,4-OXADIAZOLE The present invention relates to novel derivatives ofZ-hydroxymethyl-l ,3,4-Xadiazole, their process of preparation and theirtherapeutic application.

The novel derivatives according to the invention correspond to thegeneral formula I:

no 'CH 0 (II) with a phenylhydrazide of formula III:

in which R and n have the same significance as in formula (l) and,possibly, by reacting the resultant compound of formula IV:

with a compound selected from:

an alkyl isocyanate of formula V:

(IIi) 01 coo Q this latter reaction producing the compound of formulaVII:

which is subsequently treated with liquid ammonia.

The reaction between the compounds of formulas -(IV-)arid (V) is carriedout under pressure and at a 5 .temperature between 100 and 120C.

The following preparations are given by way of exam- 7 plesto'illustr'ate the invention.

EXAMPLE 1 2-Hydroxymethyl-5-phenyll ,3 ,4-oxadiazole (Code No. 71558) 68g (0.5 mol) of phenylhydrazide dissolved in 600 c.c. of anhydrousethanol (distilled under sodium) are rapidly introduced at ambienttemperature and with good agitation, to a solution of 84 g (0.6 mol) ofethyl hydroxyacetimidate hydrochloride in 600 c.c. of anhydrous ethanol.The mixture is kept at ordinary temperature for 15 minutes, and is thenheated for 1 hour with boiling.

The ammonium chloride formed is dried and the filtrate is concentratedunder reduced pressure by distilling off two-thirds of the alcoholutilised. The product crystallises, isdried, washed with water and thenwith isopropyl ether. It is purified by recrystallisation from absolutealcohol. 1 v

Melting point 127C Yield 89% g Empirical formula C H N Og Elementaryanalysis:

C H V N Calculated"): 61.36 4.58 15.90 Found '71 61.31 4.75 16.04

EXAMPLE 2 Aminocarbonyloxy-Z-methyl-5-phenyll ,3 ,4- oxadiazole (CodeNo. 7209 The phenylcarbonate of the compound of Code No. 71558 preparedby Example], is prepared in a first stage. For 16 16g (0.1 mol) ofphenylchloroformate is introduced into a solution, cooled to 5C, of 18 g(0.1

of dry pyridine.

The preparation is maintained at ambient temperature for 12 hours andthen the pyridine is evaporated under vacuum. The product obtained offormula (VII) (11 0), is dissolved 200 200cc of ethyl acetate and thesolution is washed with 2N hydrochloric acid, and then with a solutionof sodium bicarbonate.

After evaporation of solvent, the product is sufficiently pure.

mol) of said compound of Code No. 71558 in 200 c.c.

from 250 c.c. of 96 alcohol.

Melting point 149C Yield 90% Empirical formula C H N O Elementaryanalysis:

c H N Calculated 54.79 4.14 19.17 Found 71 55.02 4.29 19.14

EXAMPLE 3 2-Methylaminocarbonyloxymethyl-S-phenyl- 1 ,3,4- oxadiazole(Code No. 71574) A solution in 250 c.c. of anhydrous benzene of 18 gtively.

TABLE I N -N 11 Code (R 2 n Empirical Molecular Melting Yield Elementaryanalysis No. Formula Weight Point (71) Calculated (71) Found (71) (C) CH N C H N H C 72460 C H N O 190.20 82 78 63.15 5.30 14.73 63.23 5.4114.53

72415 c c,,,11,.,1-1 o 190.20 108 64 63.15 5.30 14.73 63.12 5.46 14.93

72349 Cl C,,H Cl N 0 210.62 127 51.32 3.35 13.30 51.44 3.44 13.39

F 72130 C,,H F N 0 194.16 118 60 55.67 3.63 14.43 55.88 3.87 14.23

72329 F 0 C,,H F N 0 194.16 60 55.67 3.63 14.43 45.88 3.66 14.46

F C 72293 C H F N- O 244,17 126 81 49.19 2.89 l 1.47 48.99 .91 1 1.51

CI 72132 cl C,,H,;C1 N O. 245.07 184 91 44.1 1 2.47 11.43 44.02 2.36 11.26

721 15 H CO c,.,H,.,N o.. 206.20 146 87.5 58.25 4.89 13.59 58.23 5.0713.50

H CO 72357 H CO G c H N Q, 36.22 60 55.93 5.12 11.86 56.10 5.21 11.86

H CO I 72403 H CO-D C H N O 66. 5 60 54.13 5.30 10.52 53.93 5.28 10.60

H CO

72845 C,,H;Cl N 0 210.62 105. 57 51.32 3.35 13.30 51.60 3.37 13.45

72846 Cml-l N o 206.20 86 50 58.25 4.89 13.59 58.08 4.91 13.61

(0.1 mol) of the compound of code No. 71558, prepared by example I, and9 g (0.15 mol) of methyl isocyanate is heated for 5 hours at 100C in anautoclave.

After evaporation of the solvent, the product obtained is recrystallisedfrom 100 c.c. of isopropyl alcohol.

1O Melting point l 14C Yield 86% Empirical formula C H N O 15 Elementaryanalysis:

Calculated 56.65 4.75 18.02 Found 56.56 4.84 17.85

The compounds listed in the following Tables 1, 11 and 111, have beenprepared according to the method of operation described in Examples 1, 2and 3 respec- Melting Elementary analysis Code (R Empirical MolecularYield 2 11 No. formula weight point (7:) Calculated (70 Found (70) c H Nc 1-1 N F3C 72371 C H F N Q, 301.22 138 88 47.84 3.35 13.95 47.87 3.34.14.15

CI 72372 D- C,,H,,CI N,,O;, 302.12 141 68 43.73 3.00 13.91 43.53 2.9313.78

72383 H3CO- C H.;,N;,O., 263.25 106 70 54.75 4.98 15.96 54.55 4.94 16.03

H3CO

72384 C, H,,.,N,,0,-, 293.27 116 87 53.24 5.16 14.33 53.28 5.14 14.19

H3CO 72434 H co.- C H N O 323.30 125 95 52.01 5.30 13.00 51.98 5.3413.03

c1 730069 C,,H ,ClN,-,O 267.67 82 59 49.36 3.77 15.70 49.39 3.65 15.82

730085 c n N o 263.25 92 60 54.75 4.97 15.96 54.63 4.85 16.02

OCH3

The compounds of formula (I) have been tested on TABLE V animals in thelaboratory and have been shown to pos- Painful washings Caused byinjection of sess analgeslc, antunflammatory, antlconvulslvant,phenylbenzoquinone 1 Code No. of Dose administered Percentagetranqurlrsmg, myorelaxant, antidepresslye, vasodllata compoundtested(mglkg/pol) reduction of tory, d1uret1c, antr-ulcerous, antlarythmrc,antlserotonumber f i f l ninic, spasmolytic, hypotensive,antibronchoconstricstremhmgs tive, anticholinergic and antiemeticproperties. 73293 100 80 l. Analgesic properties D 72339 50 100 c m offrm I admi "ter l A The 0 pounds 0 uld ed by Ora 2. Antunflammatoryproperties means to the mouse, are capable of reducing the num- 40 berof painful stretchings caused by the intraperitoneal injection of aceticacid or phenylbenzoquinone.

By way of example, there are listed in the following Tables IV and V thepercentage reduction in the number of painful stretchings followinginjection of acetic acid and phenylbenzoquinone, respectively, thesepercentages being obtained by administration of different compounds offormula (I).

TABLE IV Painful strctchings caused by injection of acetic acid Code Noof compound tested Dose administered (mg/kg/p.o.)

Percentage reduction of number of painful These properties are shown bya diminution of the local oedema caused by the sub-plantar injection ofa phlogogenic agent, such as carraghenin, in the rat following the oraladministration of compounds of formula (I).

By way of example, the results obtained by administration of differentcompounds of formula (I), are listed in the following Table VI.

TABLE IV-continued Code N0. of Dose Percentage reduction compound testedadministered of oedema (mg/kg/po) 3. Anticonvulsivant, tranqpilising andmyorelaxant properties. j

The compounds of formula (1), pr jentively administered by oral means tothe mouse, reduce the mortality provoked by the sub-cutaneous injectionof cardiazol and strychnine.

The following Table VII gives, by way of example, the results obtainedby administration of different compounds of formula (I). 1

4. Hypotensive properties Administered by intraveinous means to theanaesthetised rat, the compounds of formula (1) cause a lowering of thearterial pressure.

The activity of compounds of formula (I) in this domain, may beappreciated by referring to the following Table V111, which set forththe results obtained by the administration of different compounds offormula (1).

TABLE VIII Code No. of Dose Percentage Duration of compound administeredreduction of effect tested (mg/kg/iiv) arterial pressure (mn) 5.Antibronchoconstrictive and anticholinergic properties Injected byintraveinous or intraduodenal means, the compounds of formula (1) arecapable of opposing the bronchoconstriction provoked in the guinea-pigby the intraveinous injection of acetylcholine and evaluated by theKonzett method.

By way of example. the results obtained by administration of differentcompounds of formula (I) are listed in the following Table IX.

TABLE IX Code No. of Percentage compound Dose administered inhibition oftested bronchoconstriction 72357 1 mg/kg/Lv. 100 72403 100 mg/kg/i.d. 5072293 100 mg/kg/id 50 72130 100 mg/kg/i.d. 72349 100 mg/kg/id 50 72424100 mg/kg/id 100 72445 100 mg/kg/id 50 71574 2 mg/kg/i.v. 50 72372 100mg/kg/i.d. 50 72434 100 mg/kg/id. 70 72443 100 mg/kg/id. 50 72674 100mg/kg/i.d. 50 100 mg/kg/i.d. 50 100 mg/kg/i.d. 100

6. Antidepressive properties The compounds of formula (I), preventivelyadministered by oral means to the mouse, are capable of opposing theptosis provoked by the injection of reserpine.

By way of example, the administration of 100 mg/kg/p.o. of the compoundof code No. 72293 produced a reduction of 45% in the ptosis provoked byreserpine on the mouse.

7. Vasodilatatory properties The compounds of formula (I) are capable ofaugmenting the flow of the coronary vessels of the isolated heart of aguinea-pig, when said compounds are added in the perfusion liquid ofsaid organ.

By way of example, there is listed in the following Table X, the resultsobtained by the administration of different compounds of formula (I).

TABLE X Code No. of Concentration in Percentage augmentation compoundperfusion liquid of flow of heart tested (pg/m1) TABLE XI Code No. ofPercentage augmentation compound of urinary elimination tested TABLEXI-continued Code No. of Percentage augmentation compound of urinaryelimination tested TABLE XII Code No. of Percentage reduction ofcompound tested ulcers 10. Anti-arythmic properties Administered byintraperitoneal means, the compounds of formula (I) are capable ofprotecting the mouse against the ventricular fibrillations provoked bythe inhalation of chloroform.

By way of example, there is specified in the following Table XIII the DE50 of different compounds of formula (I).

TABLE XIII Code no. of DE. 50

compound (mg/kg/ip) tcstcd I l. Antiserotoninic properties The compoundsof formula (I), administered by intraveinous means, are capable ofopposing the bronchoconstrictural effects of the intraveinous injectionof serotonine, these effects being evaluated by the Konzett and Rosslertests, on the guinea-pig.

By way of example, the administration of l mg/kg/i.v of the compound ofcode No. 72516 permits a reduction of 100% on the bronchoconstricturaleffects of serotonine.

12. Spasmolytic properties The compounds of formula (I), introduced inthe conserving medium are capable of opposing the contractural action ofbarium chloride on the isolated duodenum of the rat. This activity isevaluated by taking papaverine as standard.

By way of example, the compound of code No. 72443 presents an equivalentactivity to that of papaverine.

l3. Antiemetic properties The compounds of formula (I), administered byoral means, permits a reduction in the vomitings provoked by apomorphinein the dog.

By way of example, the administration of 10 mg/Kg/p.o. of the compoundsof code nos. 72132 and 72329 permits a 50% reduction in the vomitingscaused by apomorphine.

As a result of a comparison between the pharmacologically active dosesmentioned above and the lethal doses listed in the following Table XIV,the difference between said doses is sufficiently great to permit theutilisation of the compounds of formula (I) in therapeutics.

TABLE XLV Code No. Dose administered Percentage of compound listed(mg/KG/p.o.) mortality to the mouse (71.)

71558 1 400 E50 72357 1 600 '='50 72403 2 000 '=-10 72293 2 200 E50 72115 2 000 0 72130 2 200 =50 72132 I 700 50 72329 I 200 =50 72415 2 500'='50 72460 2 000 510 72349 1 300 E50 7209 3 000 50 72410 I E50 72424 2000 0 72220 2 500 50 72445 2 200 E50 72435 2 000 0 72467 2 000 0 72468 2000 0 72516 2 000 0 72527 1 200 E50 71574 2 100 E50 72371 2 000 0 723721 600 250 72434 4 400 E50 72443 l 100 E50 72383 2 000 0 72384 1 800 E5072519 I 500 E50 72674 2 000 0 72607 2 000 0 72562 I 850 E50 Thecompounds of formula (I) are useful in the treatment of diverseoriginating pains, painful inflaminations, hypertensions, epilepsy,anxiety, contractures, asthma, visceral spasms, gastroduodenal ulcers,depressions, circulatory insufficiencies, oedemas, cardiac arythmies andmigraines.

They may be administered by oral means in the form of tablets, gelulesand dragees containing 25 to 400 mg of active ingredient (1 to 5 times aday), in the form of drinkable drops in doses of 0.2 to 2% (30 to 100,three times a day) and in the form of syrup in a dose of 0.2 to 2% (3 to6 spoonfuls a day), by parenteral means in the form of injectableampoules containing 1 to mg of active ingredient (l or 2 per day) and byrectal means in the form of suppositories containing 25 to 400 mg ofactive ingredient (l or 2 times a day).

Accordingly, the present invention also relates to a therapeuticcomposition comprising a compound of the general formula (I) togetherwith a therapeuticallyacceptable carrier.

What we claim is:

l. A compound of the formula:

n l W CH O-R wherein:

R is hydrogen, aminocarbonyl or aminocarbonyl N substituted by alkylhaving up to 4 carbon atoms, R is halogen, alkoxy having up to 4 carbonatoms,

alkyl having up to 4 carbon atoms, or trifluoromethyl, and nisO, 1,2or3.2. A compound of claim 1, in which R is hydrogen. 3. A compound of claim1, in which R is aminocarbonyl.

4. A compound of claim 1, in which R is N-methyl aminocarbonyl.

5. A compound of claim 2, in which R is chloro or fluoro.

6. A compound of claim 2, in which R is methyl.

7. A compound of claim 2, in which R is methoxy.

8. A compound of claim 5 in which n is 2 or 3.

9. A compound of claim 3, in which R is chloro or fluoro.

10. A compound of claim 4, in which R is chloro or fluoro.

11. A compound of claim 3, in which R is methyl.

12. A compound of claim 4, in which R is methyl.

13. A compound of claim 3, in which R is methoxy.

14. A compound of claim 4, in which R is methoxy.

15. A compound of claim 9 in which n is 2 or 3.

16. A compound of claim 10 in which n is 2 or 3.

17. A compound of claim 7 in which n is 2 or 3.

18. A compound of claim 13 in which n is 2 or 3.

19. A compound of claim 14 in which n is 2 or 3.

1. A COMPOUND OF THE FORMULA:
 2. A compound of claim 1, in which R1 ishydrogen.
 3. A compound of claim 1, in which R1 is aminocarbonyl.
 4. Acompound of claim 1, in which R1 is N-methyl aminocarbonyl.
 5. Acompound of claim 2, in which R2 is chloro or fluoro.
 6. A compound ofclaim 2, in which R2 is methyl.
 7. A compound of claim 2, in which R2 ismethoxy.
 8. A compound of claim 5 in which n is 2 or
 3. 9. A compound ofclaim 3, in which R2 is chloro or fluoro.
 10. A compound of claim 4, inwhich R2 is chloro or fluoro.
 11. A compound of claim 3, in which R2 ismethyl.
 12. A compound of claim 4, in which R2 is methyl.
 13. A compoundof claim 3, in which R2 is methoxy.
 14. A compound of claim 4, in whichR2 is methoxy.
 15. A compound of claim 9 in which n is 2 or
 3. 16. Acompound of claim 10 in which n is 2 or
 3. 17. A compound of claim 7 inwhich n is 2 or
 3. 18. A compound of claim 13 in which n is 2 or
 3. 19.A compound of claim 14 in which n is 2 or 3.